Tetrahydropyrimidine compounds



l atentecl July 25, 1950 TETRAHYDROPYRIMIDINE COMPOUNDS AND METHOD FOR THEIR PREPARA- TION Vernon E. Haury, Simi, Calif., assignor to Shell Development Company, San Francisco, Calif., a corporation of Delaware No Drawing. Application September 3, 1948, Serial No. 47,746

- 16 Claims.

This invention relates to tetrahydropyrimidine compounds and to a method for preparing the same by reacting ammonia and a monoketone in the presence of an acidic condensation catalyst. The term tetrahydropyrimidine is employed herein to designate those compounds of the general formula 'dineco'mpounds may be produced by reacting a monoketone with'ammonia in the presence of an acidic condensation catalyst, the reaction proceedingaccording to the following general equa- For example, it has been discovered that by reacting a ketone such as acetone with anhydrous ammonia at a suitably elevated temperature and in the presenceof an acidic condensation catalyst such'as'hydrochloricacid or zinc chloride, there is obtained the highly alkylated pyrimidine compound '2,2,4,4,6 pentamethyl-2,3,4,5-tetrahydropyrimidine. Inasmuch as all of the tetrahydropyriniidine compounds referred to herein are of the 2,3,4,5 -tetrahydro variety, for convenience of description these numerals will hereinafter be omitted both when naming particular compounds as well as in referring to tetrahydropyrimidines generally.

The ketones which may be employed as reactants in carrying out the process of the present invention are the monocarbonyl compounds wherein the carbonylic carbon atom and an adjacent (alpha) carbon atom hearing at least one hydrogen atom are members of an open-chain of carbon atoms. Such ketones may be represented by the general structural formula RCOCH R1 R2 wherein R represents a monovalent organic radical, preferably hydrocarbyl in nature, and R1 and R2, which may be the same or different, are selected from the group consisting of the hydrogen atom and monovalent organic radicals, which again are preferably of the hydrocarbyl variety. A still more preferred class of ketone reactants comprises that wherein R is an alkyl radical and R1 and R2 are either hydrogen atoms or alkyl radicals. Thus, representative hydrocarbyl groups which R, R1 and R2 (when not hydrogen) may represent are alkyl radicals such as methyl, ethyl, n-propyl, isopropyl, the various butyl, amyl hexyl, heptyl and octyl radicals; aralkyl radicals such as the benzyl, methyl benzyl; phenyl ethyl, phenyl propyl, and naphthyl methyl radicals; alkaryl radicals such as the methyl phenyl, ethyl phenyl, propyl phenyl, methyl naphthyl, and ethyl naphthyl radicals; aryl radicals such as the phenyl, methyl naphthyl, and ethyl naphthyl radicals; aryl radicals such as the phenyl and naphthyl radicals; cycloparaflinic or cycloaliphatic hydro- I" carbon radicals such as cyclopentyl, methyl cyclopentyl, dimethyl cyclopentyl, ethyl cyclopentyl, cyclohexyl, methyl cyclohexyl, polymethyl cyclohexyl, and propyl cyclohexyl radicals. These radicals may contain substituents such as the hydroxyl, nitro, or halogen atoms provided that the substituent group is of a kind and in such a position in the molecule as not to interfere with the eifective practice of the process of the invention. Thus, suitable substituted radicals are the hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyphenyl, hydroxynaphthyl, hydroxycyclopentyl, hydroxycyclohexyl, nit r 0- methyl, nitrophenyl, chloromethyl, chloroethyl and bromophenyl radicals.

It will be realized that the particular ketone reactant selected will depend on the tetrahydropyrimidine compound it is desired to prepare. Thus, the following table illustrates the preparation of particular tetrahydropyrimidine compounds by reaction of ammonia with the approacidic condensation-type catalysts. Appropriate compounds coming within the scope of this Kctone Reactant 'letrahydropy'rimidine Product Acetone 2,2,4,4,6-pentamethyltetrahydropyrimidine.

diethyl ketone .l 2,2,4,4,6pentaethyl--methyltetrahydropyrimidine. Methyl ethyl ketone 2,4 dimethyl-2,4,6-triethyltctrahydropyrimidine.

methyl propyl ketone ZA-dimethyl-Zi,(S-tripropyltetrahydropy-rimidine. methyl octyl ketone. 2,4-dimethyl-2, ifi-trioctyltetrahydropyrimidine. Acetophenone i 2,4-dimethyl-2,4;6-triphenyltetrahydropyrimidine. Methyl benzyl ketone. 2,4-dimetliyl-2,i,G-tribenzyltetmhydropyrimidine. Ethyl bcnzyl ketone .l 2,-dicthyl-E-methyl-ZA,6-tribenzyltetrahydropyrimidine.

Methyl orthcchlorobenzyl ketone Methyl betachloroethyl ketone" Methyl 3-hydroxypropyl kctone Isopropyl phenyl ketonc Ethyl alpha-methylbenzyl ketonenp 2,4-dimethyl-2,4,6-triorthcchlorobenzyltetrahydropyriinidine. 2,i-dimethyl-2,4,6-tribetachloroethyltetrahydropyrimidine. 2,'4 -dimethyl-2, i,6-tri- (3-hydroxylpropyl) -te'trahydropyrimidine. 2g4-isopropyl 5$-dimethyl-2,4,6-tripheny1tctrahydropyrimidine. 2,i-dialpha-methylbenzyl-fi-methyl-5-phenyl-2,4,c-triethyltetrahydropyrimidine.

While a wide variety of ketones be substituted for those set forth in the preceding table with the production of a corresponding tetrahydropyrimidine, a particularly valuable class of tetrahydropyrimidines is that whose members are 'prep'ar'ed'by reacting with ammoniafln the presence Oran acidic condensation catalyst, a monoketone containing from 3 to carbon atom in the molecule and having only hydrocarbyl groups attached to the carbonyl carbon atom. Such pyrimidines may be defined as tetrahydropyriinidin'es containing from 9 to carbon atoms in the molecule and having a total of at least fi've separate hydrocarbyl groups attached'to'not .l es'sthan 3 diiierent carson'smms of the (2,3,4,5) tc'trahydropyrimidine nucleus, said nucleus being regarded'as having the structure at least-one of which is the methyl radical, at-

:tached to the carbonyl carbon atom. In other words, suchketones are those wherein, in the general formula RCOQH(R1)-R2, R1 and Re are hydrogen atoms andR isan alkyl radical of from 1 to 8 carbon atoms. Representative tetrahydrcpyrimidines coming within this more preferred class are: 2,2,4,4,6 pentamethyltetrahydropyrirnidine; 2,4-dimethyl-2,4,6-triethyltetra-= hydropyrimidine; 2,4-dimethyl-;2,4,6 tripropyltetrahydropyrimidine; 2,4-dimethyl-2,4,6-triisoprcpyltetrahydropyrimidine; 2,4dimethy1-2,l,6- tributyltetrahydropyrimidine; 2,4 dimethyl- 2,4,6-trioctyltetrahydropyrimidine. These compounds may be generically referred to as 2,4-dimethyl-2,4,6-trialkyltetrahydropyrimidines containing from 9 to 30 carbon atoms in the'molecule.

The catalyst necessarily employed in carrying out the process of this invention comprises one or more of the compounds generally termed term are acids 7 themselves, as CHaCOOH, '(CUOH)2, I-lCl, I-INOa, H2SO4, 1-181 and H1304, for example, or compounds such as ZnClz, F8013, NHiCi or CaClz which give an acid reaction in aqueous solution The amount of catalyst used may be varied'depending on 'ajnuin'ber oi factors,

inducing the time and tem erature or reaction as well as the nature of the particular 'ketone reactant and catalyst selected. However, 'goofd results have been obtained'through use of from 0.0001 to 8.1, and'preferably of from D2001 ti; 0.01, mole of catalyst per mole of ketoiie reactant. The reaction will proceed to a limited extent with even smaller amounts of catalyst, though with total elimination or catalyst the production of tetrahydropyrimidine "product may be regarded as negligible. Thus, reaction of 20 moles of acetone with 16 moles of ammonia for 4 hours at 60 to 70 C. Without catalyst yielded less than 10 grams of 2,14,45-pentamethyltetrahydropyrimidine, whereas the same process when conducted in the presence of 0.01 mole of concentrated hydrcchlcric acid'resulted in the conversionof iroin to of the acetonefto the desired 2,2,43,8- pentamethyltetrahydrobyrimidine product. ther, while larger amounts of catalyst than 0.1 mole per mole of 'ketone rea'ctantmay be used Without harmful results, such additions are normally unproductive of further benefit.

As has been md'cated in the general equation given above, the ammonia and ketone reactants combine in the ratio ci il-.66 mole of ammonia for each mole of ketone. Nevertheless the reaction goes forward in aneificient manner even with one or the other of the reactants in stoichioinetric excess Thus, goodresults havebeenobtained through use of from 0.25 t'o 1.5 moles of ammonia. per mole ofsketcne; and the preferred practice is to supply the reactants in an ammonia r am mole ratio which may vary from about 0.5 to about 1.

While the ammonia and ketene may be brought into reactive engagement in the presence of the acidic catalyst in any desired manner, the preferred practice is to bring'arihydrous'ammonia into contact with the liquid keton'e, the latter being present either as a naturally occurring liquid or dissolved in an appropriate inert solvent, as h'exane, dioxane, or the like, in which liquid the catalystisalso present Under these conditions the reaction proceeds slowly at room temperatures and pressures, though the'same is greatly accelerated at superatmospheric pres sures, and to a-lesser extent-,by heating. When superatmospheric pressures 'are used; the pres sure should be sufiiciently great to efl'ect solution in the liquid ketone of a substantial porticn of the ammonia present Thus, whereas pressures of but 3 to 5 atmospheres will normally s1 1 I-' fice for this purposeat reaction temperatures b mimosa tween 20 and 50 0., much higherpressuresas to 50" or more atmospheres, will be required at temperatures above 75 C.- and particularly above 100 C. Asconcerns'the reaction temperature, a suitable range is from to 150 (3., though a preferred range is from to 100 0. However, the use of lower and even higher temperatures than those here indicated is entirely permissible, though-below 15 C. the reaction becomes unduly slow, whereas above 150 C. the quantity of byproducts formed is often excessive.

--The required reaction time commensurate with relatively complete reaction will vary depending uponthe conditions prevailing in the reaction zone. However, within thetemperature range of from 15 to 150 C.', and at superatmospheric pressures effective to'maintain a substantial portion of the ammon'ia' present in solution in the liquid ketone, for which purpose pressures of from-3 to 50 atmospheres are generally satisfactory, reaction periods of from to 5 hours will normally suflice. For example, a-reaction which goes to completion in approximately2 hours at 100 C. will normally require about 3 hours at C. and from 4% to 5 hours at 15 C. When conducting the operation in a batchmanner in the liquid phase and in a closed system at superatmospheric pressures, progress of the reaction is generally evidenced by a gradual pressure drop, the reaction being deemed complete when the pressureremains at a fairly constant level for an'appreciable'leng'th of time.-

The tetrahydropyrimidine product may 'be recovered from the reaction mixture by any suitable means such as fractional distillation, treatment with selective solvents, or the like. However, fractional distillation is the preferred'separation method and when practiced requires that the material to be distilled be first separated from any water present. Thisdehydration may be effected, for example, by the addition of caustic in either the solid and concentrated form, with the organic material to be distilled being drawn off as an anhydrous upper layer. An alternative dehydration method is to dilute the reaction mixture with benzene or other appropriate hydrocarbon; the upper, organic layer is then separated from the aqueous layer, following which it is neutralized and distilled, neutralization being here an essential step.

The novel tetrahydropyrimidines prepared according to the process of this invention have a wide field of utility. In addition to possessing medicinal properties generally, they also serve as valuable intermediates in the preparation of other chemical compounds. Thus, in copending application, Serial No. 736,610, filed March 24, 1947, now Patent Number 2,486,648, there is disclosed a method for producing beta-diamines from tetrahydropyrimidines, whereas in copending application, Serial No. 792,847, filed December 19, 1947, now Patent Number 2,497,548, there is disclosed a method for converting tetra-hydropyrimidines into beta-amino alcohols.

The following examples illustrate certain specific embodiments of the present invention:

Example I Acetone was reacted with ammonia to produce 2,2,4,4,6-penta-methyltetrahydropyrimidine. In carrying out this reaction, 1218 grams of acetone were placed in a suitable reaction vessel together with 235 grams of anhydrous ammonia and 3 grams of concentrated hydrochloric acid. The vessel was then heated at 30:5 0. for 3 47% based on the weight of hours, the pressure within the vessel being'approximately 75 p. spi. at the start of the reaction and diminishing as the reaction progressed. The desired pyrimidine product was recovered in a yieldrof 48%, based on the amount of acetone employed, by first adding 250 grams of solid sodium hydroxide to thereaction mixture and thereafter separating ofi and distilling theresultant upper liquid layer. In similar experi ments separation was effected in an equa'llyefficient manner by diluting the reaction mixture with an equal volume of benzene, separating the resultant upper layer and thereafter distilling the same following neutralization with a dilute solution of sodium hydroxide.

' The 2,2,4,4,6-pentamethyltetrahydropyrimidine compound had a boiling point of 169 to 171 C. at atmospheric pressure (104.6 to C. at 100 mm. Hg), a refractive index '20/D of 1.4560 and a specific gravity 20/4 of 0.883.

Example II a The reaction described in the foregoing example was conducted under similar conditions except that an equivalent amount of nitric acid was substituted for hydrochloric acid as catalyst. In.-. this .case, the conversion to 2,2,4,4,6-pentamethyltetrahydropyrimidine was increased to 51 I Example III 6 It. is also possible to prepare the 2,2,4,4,6- pentamethyltetrahydropyrimidine compoundfby employing a bimolecular condensation product of acetone "such as diacetone alcoholor mesityl oxide instead of acetone itself. However, it is believed in that such products decomposed to acetone "or an acetone-like monomer during the course of the reaction, and therefore use of these condensation'products is equivalent tousing acetone'itself. Thus, 2,2AA,G-pentamethyltetrahydropyrimidine was formed by mixing 10 moles of diacetone alcohol with 13.5 moles of anhydrous ammonia and 5 grams of ammonium chloride, andreacting the mixture for 3 hours at a temperature between 40 and 50 C. andat pressures between 50 and pounds per square inch. Thedesir'ed tetrahydropyrimidine product was recovered'from the reaction mixture in a yield of diacetone alcohol employed, the recovery being efiected by the dehydration and distillation technique set forth in Example I above.

Example IV Substantially the same yields of 2,2,4,4,6-pentamethyltetrahydropyrimidine as indicated in the foregoing paragraph are obtained by substituting equivalent amounts of mesityl acid for the diacetone alcohol, the reaction conditions being otherwise the same. In this operation 2,4-dimethyl 2,4,6 triethyltetrahydropyrimidine was prepared by reacting 30 moles of methyl ethyl ketone with 26.5 moles of ammonia in the presence of 5 grams of concentrated hydrochloric acid. The reaction was conducted at room temperatures and extended over a period of 20 hours, during which time the pressure within the system varied from approximately 100 to 15 .p. s. i. The resulting reaction mixture on being dehydrated by the addition of caustic and thereafter distilled yielded 340 grams of 2,4-dimethyl-2,4,6- triethyltetrahydropyrimidine, a. compound having a boiling point (100 mm. Hg) of 151 0., a specific gravity 20/4 of 0.8867 and a refractive index 20/D of 1.4639.

Theinvention claimed is; 1 1:. The method o produc ng mmwmen amethylt ra ydrop m din said: m thod. com: prising ea tin ammon a wi h a etone n h presence of an acidic condensationcatalyst.

@ 2; 'fihemethod of cla m 1 w er in e reactants are supplied in an ammonia/acetone mole at oiof r m -5, oil; andwhereint e react on conducted at; a temperature of; romi za to mo o and a a pressureofrimm- 3 n- Q-fi$mQSr pheres for at least one-halt hour.

3. Th m ho it eparin ,2 ifii-h ntamethy te ah d on m e, said me hod; ome nrisine eac ing ammonia-w h at l a t neom: pound selected from the group CQIISiStiHQQf; ace-.- tone and ts, imo iec ar. condensation products mesityl oxide and diacetone alcohol, said reaction being conducted in the presence of an acidic ondensati catalyst,

4. The method of I producing:- 2,4-dimethyi- 2,4,6-triethyltetrahydropyrirnidine, said method comprising reacting ammonia and methyl ethyl ketone. in the presence of an acidic condensation catalyst;

5. The method of claim 4 wherein thereactants. are added in an ammonia/methyl ethyl ketone ratio 033 from 0.5 to 1, and wherein the reactionis conducted at a temperature of from to 100 C. and at a'pressure of from 3 to 50 at.- mospheres for at least one-half hour.

6. The method of preparinga. 2,4,-dimethy1- 2, 4, 6 -trialkyltetrahydropyrimidine containing from. 9 to carbon atoms in the, molecule, said method comprising reacting ammonia and, a. kietone ,oi thel eneral structure RCOCI-Ia, where R is an alkyl radical containing from 1 to 8 carhon "atoms, said reactants being added in an emmonia/ketone mole ratio of from 0.25 to 1.5, and the reaction being conducted in the presence of an acidiccondensation catalyst, at a temperature of ,f1 0m15 to 150 C., and at a superatmospheric pressure.

' '7, The method of claim 6 whereinthe reactants are added in an amm'onia/ketone ratio of from 0.5 to 1, and wherein the reaction is conductedin the presence of an acidic condensation catalyst, at a temperature of from 25 to 100 C. andat apressureof from 3 to 50 atmospheres.

8, The method of preparing a tetrahydrc: pyrimidine compound, said method comprising 8 reacting anhydrqusi ammonia; and amonoketone wherein the carbpnuliccarhontatom and.an.ad:- ia ent carhon; atom bearing at least; one hydro,- eeniatomz are .memberstoi an, open chain: of: car.- .bqnatqni saidIeactants-beine added in, anammQnia/h one mole ratio; or. f1t mQ-25to 1.5; a d

heort beinac nducteddn the presen e of anga ondens tion catalyst. at a temperature of: om; 1, o-. :5 Qi- .andata s p r m sp eric pre su e... i

9. The method; of ciaima wherein the'reacte are-adde n; an ammqniazlsetunen ratio of rom: 0:5 orandwh ein he eactioniis conducted n heipr se ceoiianiza ididcondensation etaly ttatiatemrera u e t mm c- 0-. ttest-answe ed rp mtiatow tm9phercs:-.

91E1 9 method; o mezzani e.- etr hydropyrim d n i mmundesaid:me ho om'prisi giree a e emm niaflndemonohetone where nthe carlaonylic arb n tem ndi ntadi c tcarhon atone; b ams tt e t one-hydro en: m. re mambsi fi nio en ha o arb n. oms; said reaction being-conducted-in the presence of an cid c o densa on 1 p s 1' 1 hfim thod qt a mL1 her n t e etone reactenti ontai s betwe nBr n fl ar natoms mim m 1eu1e nc1h spn rhyd ocar y -eroups attached to; the carbonyl carbon, atom,

tam. met o a m-=19 h r he ke one reaot ntzh ereenem itE Q lr RCOGHsL R hei eanalkylir d calfor irom At -8 arb na 13. As a new chemical, comppund, 2,2,4,4,6- uen ma h l mhydtopyxim din 151. a, new, chemical compound, 2 ,4-dimethy -2. r rlietra y o y imidine,

As. new chem .a: compo 7 -,d. me hyle24 6: r lk lt trah dro yr mi in 16., A, 2,im d tetrahydropyrimidinederivative qnt ining from a to .30carbon atoms,--and. havts a ota 13; at astfi; s arate. hydrocarbyl groups P attached-tenet ,1 es s, than, 3 difierent: carotid-a oms? f the-2 3tafi' m ydrqnyrimidine nmleusi.

VE NQNE; HAURY. REFERENCES? CITED Th llowi e renc s; e. f cord {in the fi ei: patent:

- Bradbury-shah, J: Chem-,Som, 1945?, 1394 4399. 

1. THE METHOD OF PRODUCING 2,2,4,4,6-PENTAMETHYLTETRAHYDROPYRIMIDINE, SAID METHOD COMPRISING REACTING AMMONIA WITH ACETONE IN THE PRESENCE OF AN ACIDIC CONDENSATION CATALYST.
 13. AS A NEW CHEMICAL COMPOUND, 2,2,4,4,6PENTAMETHYLTETRAHYDROPYRIMIDINE. 